What are the differential diagnoses for a patient presenting with pinpoint pupils?

Differential Diagnosis of Pinpoint Pupils

Pinpoint pupils (miosis) most commonly indicate opioid toxicity, but critical alternative diagnoses include pontine hemorrhage/infarction, cholinergic toxicity (organophosphates, pilocarpine), and rarely Hashimoto's encephalopathy or botulism. 1, 2, 3, 4, 5

Primary Diagnostic Categories

Opioid Toxicity (Most Common)

• Opioids produce characteristic miosis (2-3 mm diameter) through direct activation of the pupillary sphincter muscle via parasympathetic stimulation 2, 3, 6
• Peak miosis is best detected under moderately dim lighting (4-16 foot-lamberts) approximately 90 minutes after administration 2
• Critically, the pupillary light reflex remains quantifiable even during severe opioid-induced hypercarbia and hypoxia with oxygen saturation ≤85%, distinguishing this from pontine lesions 3
• The pupil displays parasympathetic dominance with robust light reflex despite sympathetic activation from respiratory depression 3

Pontine Lesions (Critical Emergency)

• Bilateral pontine hemorrhage or infarction causes pinpoint pupils (1-2 mm) with absent or severely diminished light reflexes 5
• Associated findings include altered consciousness, quadriparesis, and "locked-in" syndrome 5
• Urgent non-contrast head CT is required to assess for hemorrhage and mass effect, followed by MRI if CT is negative 1
• Absence of corresponding pontine lesions on MRI should prompt consideration of alternative diagnoses 5

Cholinergic Toxicity

• Organophosphate poisoning and cholinergic medications (pilocarpine, physostigmine) cause miosis through excessive parasympathetic stimulation 4
• Accompanied by SLUDGE syndrome: Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis 4
• Topical pilocarpine for glaucoma treatment produces localized miosis 4

Drug-Induced Miosis (Other Medications)

• Phenothiazines and other antipsychotics can cause pupillary constriction through anticholinergic and dopaminergic effects 4
• Alpha-2 agonists (clonidine, dexmedetomidine) produce miosis through central sympathetic inhibition 4

Rare but Important Causes

Hashimoto's Encephalopathy

• Can present with bilateral pinpoint pupils without light reflex mimicking pontine infarction, but MRI shows no corresponding pontine lesion 5
• Elevated anti-thyroglobulin (anti-TG) and anti-thyroid peroxidase (anti-TPO) antibodies are diagnostic 5
• Elevated CSF protein (>100 mg/dL) without pleocytosis supports diagnosis 5
• Symptoms may improve spontaneously within 3-6 days, but corticosteroid therapy is indicated for persistent cases 5

Botulism

• Fixed, non-reactive pupils occur in 24% of confirmed botulism cases and represent a recognized clinical criterion 1
• Pupils may be dilated or constricted, but lack of reactivity is the key finding 1

Acute Angle-Closure Crisis

• Mid-dilated (4-6 mm), oval-shaped, poorly reactive or non-reactive pupil in the affected eye during acute attack 7
• Associated with severe eye pain, conjunctival hyperemia, corneal edema, and elevated intraocular pressure 7
• Gonioscopy reveals closed anterior chamber angle, distinguishing this from other causes 7

Diagnostic Algorithm

Step 1: Assess Pupil Reactivity and Size

• Reactive pupils (2-3 mm): Consider opioid toxicity first 2, 3
• Non-reactive or poorly reactive pupils (1-2 mm): Consider pontine lesion, botulism, or Hashimoto's encephalopathy 1, 3, 5
• Unilateral mid-dilated non-reactive pupil: Consider acute angle-closure glaucoma 7

Step 2: Evaluate Associated Symptoms

• Respiratory depression, altered consciousness, track marks: Opioid toxicity 3
• Quadriparesis, locked-in syndrome, cranial nerve deficits: Pontine lesion requiring urgent CT 1, 5
• SLUDGE symptoms, recent pesticide exposure: Organophosphate poisoning 4
• Descending paralysis, dysphagia, diplopia: Botulism 1
• Severe eye pain, vision loss, conjunctival injection: Acute angle-closure 7

Step 3: Obtain Targeted Imaging

• Non-contrast head CT immediately for suspected pontine hemorrhage or acute neurologic emergency 1
• MRI brain with and without contrast for subacute presentations without clear etiology 1, 5
• Gonioscopy and IOP measurement for suspected angle-closure 7

Step 4: Laboratory and Specialized Testing

• Urine drug screen for opioids and toxicology panel 2, 3
• Serum cholinesterase levels for organophosphate exposure 4
• Anti-TG and anti-TPO antibodies if MRI negative with unexplained bilateral pinpoint pupils and encephalopathy 5
• Lumbar puncture with elevated protein supports Hashimoto's encephalopathy 5

Critical Pitfalls to Avoid

• Do not assume pinpoint pupils always indicate opioid toxicity—pontine hemorrhage is immediately life-threatening and requires urgent imaging 1, 5
• Do not rely solely on pupil size; assess light reflex carefully, as preserved reflex strongly suggests opioid toxicity rather than structural brainstem lesion 3
• Do not overlook Hashimoto's encephalopathy in patients with negative MRI but persistent symptoms—check thyroid antibodies 5
• Do not miss unilateral presentations—acute angle-closure presents with unilateral mid-dilated non-reactive pupil, not bilateral pinpoint pupils 7